This application is a 371 of PCT/EP99/10468, filed Dec. 30, 1999.
The present invention relates to the use of derivatives of the ((aminoiminomethyl)amino)alkane-carboxamide type in the treatment of pathologies associated with insulin resistance syndrome.
The present invention therefore provides pharmaceutical compositions comprising as active principle a compound of general formula (I) 
in which:
R1 is selected from one of the following groups:
H;
(C1-C20)alkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
R2 and R3 are selected independently from
H;
(C3-C8)cycloalkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
(C3-C8)heterocycloalkyl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14) aryl, (C6-C14) acyl or (C1-C5) alkyl group;
(C6-C14)aryl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, halogen, (C1-C5)alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl, cyano;
(C1-C13)heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, halogen, (C1-C5)alkyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5) alkylamino, trifluoromethyl, cyano; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14)acyl or (C1-C5) alkyl group;
(C6-C14)aryl-(C1-C5)alkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano;
and A is selected from the groups:
xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CHR4xe2x80x94,
R4 being selected from:
H;
(C1-C20) alkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
(C3-C8)cycloalkyl substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
(C3-C8) heterocycloalkyl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5) alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14) aryl, (C6-C14) acyl or (C1-C5) alkyl group;
and their solvates and pharmaceutically acceptable salts.
The heteroaryl groups are selected in particular from pyridyl, pyrimidinyl, furyl, pyrrolyl, thienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, indolyl, benzofuryl and imidazolyl.
The heterocycloalkyl groups are selected in particular from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl and tetrahydropyranyl.
A preferred group of compounds of formula I is constituted in which R1 is H or (C1-C6)alkyl.
A preferred group of compounds of formula I is constituted in which:
R2 is selected from
(C3-C8) cycloalkyl substitued or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5) alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
(C6-C14) aryl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5)alkoxy, (C1-C5) alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano;
(C1-C13) heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5) alkylamino, trifluoromethyl, cyano;
a nitrogen atom can additionally be substituted by a (C6-C14) aryl, (C6-C14) acyl or (C1-C5) alkyl group.
A particularly preferred group of compounds of formula I is constituted in which R2 is selected from a (C6-C14) aryl group possibly substituted as defined above.
To the knowledge of the Applicant, the compounds of formula (I) are novel with the exception of xcex1-guanidinoacetanilide, which is described by Mazundar (Indian Drugs 1989, 27, 5, 292), i.e. the compound of formula I in which R=H, R2=phenyl and R3=H.
The invention also relates to the tautomeric forms, to the enantiomers, diastereoisomers and epimers of the compounds of general formula (I).
The compounds of general formula (I) have basic nitrogen atoms and can be monosalified or disalified by mineral or organic acids.
The compounds of formula (I) can be prepared by reacting a compound of formula: 
with a compound of formula: 
in which:
R5 is selected from xe2x80x94SCH3, pyrazolyl or xe2x80x94SO3H, and
T is a tert-butyloxycarbonyl or benzyloxycarbonyl protective group.
The compounds of formula (II) can be prepared in accordance with a process in which:
a) a compound of formula: 
xe2x80x83in which R2 and R3 are as defined above is reacted with an acyl halide of general formula (VI): 
in which:
A is as defined above,
L represents a chlorine or bromine atom or an activated ester form,
Z represents a chlorine or bromine atom or a protected amino group, to form a compound of general formula (VII): 
xe2x80x83in which R2, R3, A and Z are as defined above;
b) the compound of general formula (VII) is reacted with potassium phthalimide and then with hydrazine monohydrate or else with a nitride followed by a reduction to form a compound of general formula (II) in which R1=H.
In the case where Z is a protected amino group, it is appropriate to deprotect it at this stage to form a compound of general formula (II).
The compounds of general formula (II) in which R1 is other than H can be obtained by reacting a compound of formula (VII) with an amine of general formula (VIII):
R1NH2xe2x80x83xe2x80x83(VIII).
The compositions according to the present invention are useful in the treatment of pathologies associated with insulin resistance syndrome (syndrome X).
Insulin resistance is characterized by a reduction in the action of insulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) and is involved in a large number of pathological states, such as diabetes and, more particularly, non-insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia, obesity, arterial hypertension, and certain microvascular and macrovascular complications such as atherosclerosis, retinopathies and neuropathies.
In this context, reference may be made, for example, to Diabetes, Vol. 37, 1988, 1595-1607; Journal of Diabetes and its complications, 1998, 12, 110-119, or Horm. Res., 1992, 38, 28-32.
In particular, the compositions of the invention exhibit a strong hypoglycaemic activity.
The compositions according to the present invention can also be used for treating the chronic complications due to the formation of xe2x80x9cadvanced glycosylation end productsxe2x80x9d, written AGEs, which result from the glycoxidation reaction between glucose, its oxidation derivatives and the amino functions of proteins, including the so-called Maillard reactions of glycation of glyoxal for example.
The pharmaceutical compositions according to the invention can be provided in forms which are intended for parenteral, oral, rectal, permucous or percutaneous administration.
They will therefore be provided in the form of solutions or suspensions for injection or multi-dose bottles, in the form of plain or coated tablets, film-coated tablets, wafer capsules, gelatin capsules, pills, cachets, powders, suppositories or rectal capsules, or solutions or suspensions for percutaneous use in a polar solvent or for permucous use.
The excipients which are suitable for such administrations are derivatives of cellulose or microcrystalline cellulose, alkaline earth metal carbonates, magnesium phosphate, starches, modified starches, and lactose for the solid forms.
For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients.
For parenteral use, water, aqueous solutions, physiological saline and isotonic solutions are the vehicles used most judiciously.
The dosage can vary within wide limits (from 0.5 mg to 1000 mg) depending on the therapeutic indication and the administration route, and also on the age and weight of the individual.